The goal of the project is to develop the first disease-modifying, non-hormonal therapeutic for endometriosis (EMS). EMS is considered the greatest overlooked epidemic in women's health, affecting approximately 10% of women worldwide. It is the number one cause of infertility and disability among adolescents and women across all ethnicities. Shockingly, to date, there is no cure for this chronic and prevalent disease. Because it takes an average US woman 6-10 years to be diagnosed with EMS, the current management protocols of hormonal, pain therapies, or surgical interventions-which fail to reverse the disease or address the root cause-are often insufficient. Hormone pills and GnRH antagonists (causing "medical menopause") prescribed to patients with EMS can induce many undesirable side effects. Many women who undergo EMS excision will have reoccurrence within 5 years of surgery. Hysterectomies are recommended for women who do not experience relief through less invasive methods. Our team has developed a novel therapeutic option for EMS by targeting a downstream component of a pathway known to contribute to endometriosis pathogenesis and endometrial migration and invasion. Our panel of macrocyclic peptides specifically inhibits this downstream component and shows success in cell potency and proliferation assays, reporter assays, serum stability, membrane permeability, toxicity mouse studies, and exhibits great potential to act as an endometriosis therapeutic. Other molecules targeting the pathway have reversed EMS progression in academic settings, but have off-target or upstream pathway targets that induce undesired side effects. In this novel project, we will identify the most promising 2 macrocyclic peptides that inhibit the migration and invasion in EMS cells and confirm its efficacy in an EMS animal model. The compounds will be evaluated for cellular potency, PK/PD, on-target effects, confirm lack of off-target effects, inhibition of cellular invasion and migration, and efficacy using primary EMS cells donated by our collaborators at the Boston Center for Endometriosis. The cells have been excised from different patients and collected in accordance to the EPHECT standard protocols with accompanying clinical records. The PK, efficacy, and biodistribution of our macrocyclic peptides will also be evaluated an in vivo animal models of endometriosis, and on-target effects will be confirmed through qPCR of RNA, immunohistochemistry, and western blot analysis. Medicinal chemistry optimization will be performed on the lead candidate peptides to obtain an optimal clinical drug profile by becoming more unnatural, peptidomimetic (small molecule-like) agents. Once validated and optimized, these compounds will enter into preclinical investigation and toxicity studies in Phase II. These experiments will prepare us for a subsequent Phase IIB application to fund IND toxicity experiments in preparation for pre-discussions with the FDA as we prepare for an IND for Phase 1 clinical trials.
Public Health Relevance Statement: The goal of this project is to develop a therapeutic capable of treating endometriosis. Endometriosis is a high priority research area of NICHD. Current management protocols for endometriosis-including hormones and surgery-do not address the root cause of the disease, fail to reverse disease progression, leave a chance of reoccurrence, and often present patients with undesirable side effects. We have identified a set of compounds that can specifically target a downstream component of a pathway known to contribute to endometriosis pathogenesis and endometrial migration and invasion, and we will develop the two most promising compound into endometriosis therapeutics.
Project Terms: Affect; Pain management; pain treatment; Pain Therapy; Pain Control; inhibitor/antagonist; inhibitor; Biological Assay; Biologic Assays; Bioassay; Assay; Western Blotting; protein blotting; Western Immunoblotting; Bone Regeneration; bone repair; Boston; cultured cell line; Strains Cell Lines; CellLine; Cell Line; membrane permeability; Cell Membrane Permeability; Nucleus; Cell Nucleus; Cell Body; Cells; Pharmaceutic Chemistry; Medicinal Chemistry; Pharmaceutical Chemistry; Clinical Trials; Crystallization; Cytoplasm; Diagnosis; Disorder; Disease; drug/agent; Pharmaceutic Preparations; Medication; Drugs; Pharmaceutical Preparations; endometriosis; Epidemic; Exhibits; Female; Future; Gene Expression; Goals; Head; Therapeutic Hormone; Endocrine Gland Secretion; Hormones; Modern Man; Human; Hysterectomy; Immunohistochemistry Staining Method; Immunohistochemistry Cell/Tissue; Immunohistochemistry; Industry; infertile; fertility loss; fertility cessation; Difficulty conceiving; Cannot achieve a pregnancy; Infertility; heavy metal lead; heavy metal Pb; Pb element; Lead; Libraries; menopausal; Female Change of Life; Menopause; Methods; Murine; Mice Mammals; Mice; Mus; Patients; Proteolytic Enzymes; Proteinases; Proteases; Protease Gene; Peptidases; Esteroproteases; Peptide Hydrolases; Peptides; Permeability; Proteins; Rats Mammals; Rat; Common Rat Strains; Rattus; Records; Research; Ribonucleic Acid; RNA Gene Products; Non-Polyadenylated RNA; RNA; Safety; Specificity; Testing; Body Tissues; Tissues; Transcription factor genes; Transcription Factor Proto-Oncogene; General Transcription Factors; General Transcription Factor Gene; Basal transcription factor genes; Basal Transcription Factor; transcription factor; Vaginal; Vagina; intravaginal ring; Vaginal Ring; Woman; Work; Female Health; Women's Health; ß-catenin; PRO2286; CUL-2; Beta-1 Catenin; Beta Cadherin-Associated Protein; beta catenin; improved; Area; Chronic; Clinical; Phase; Medical; Link; Ensure; Lesion; Endometrial; Serum; Blood Serum; disability; Disease Progression; Plant Roots; root; Funding; Ethnic Origin; Ethnicity; uptake; Critical Pathways; Critical Paths; Therapeutic; Reporter; Research Priority; programs; Investigation; Protocols documentation; Protocol; Hormonal; Operative Surgical Procedures; surgery; Surgical Procedure; Surgical Interventions; Surgical; Operative Procedures; experience; Membrane; membrane structure; peptide structure; success; Surface Plasmon Resonance; Animal Model; model organism; model of animal; Animal Models and Related Studies; Toxic effect; Toxicities; novel; member; Pathogenesis; Excision; resection; Surgical Removal; Removal; Extirpation; Abscission; Gene Proteins; Protein Gene Products; Modeling; Property; Phase I Clinical Trials; phase I protocol; phase 1 trial; Phase 1 Clinical Trials; Early-Stage Clinical Trials; pill; preventing; prevent; small molecule; Address; Dose; Affinity; Animal Testing; Gonadotropin Releasing Hormone Inhibitor; Gonadrotropin Releasing Hormone Antagonists; GnRH antagonist; National Institute of Child Health and Human Development; National Institute of Children's Health and Human Development; NICHD; in vitro Assay; in vivo; Preparation; Modification; Pathway interactions; pathway; pre-clinical; preclinical; Biodistribution; Treatment Efficacy; therapy efficacy; therapeutically effective; therapeutic efficacy; intervention efficacy; migration; peptidomimetics; peptide mimic; peptide mimetic; Cell model; Cellular model; novel therapeutics; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; mouse model; murine model; young woman; adolescent women; adolescent woman; protein biomarkers; protein markers; Pharmacology Study; Pharmacological Study; experimental study; experimental research; experiment; preclinical development; pre-clinical development; therapeutic candidate; lead optimization; lead candidate; side effect; pharmacokinetics and pharmacodynamics; PK/PD
